Translational control of human neutrophil responses by MNK1

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: cytokines;    apoptosis;    protein translation;   

DOI  :  10.1189/jlb.0113012

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Agrowingnumberofinflammatoryandimmuneprocessesinvivohavebeenshowntobeinfluencedbyneutrophil‐derivedcytokines.Whereastheunderlyingtranscriptionalmechanismsareincreasinglywellunderstood,thetranslationalregulationofthisneutrophilresponseremainslargelyunexplored.Here,weshowthattheMNK1,whichparticipatesintranslationalcontrolinseveralcelltypes,isactivatedinresponsetophysiologicalneutrophilagonists(LPS,TNF‐α)inthecytoplasmicandnuclearcompartments.Withtheuseofvariouspharmacologicalinhibitors,wefoundthatMNK1activationtakesplacedownstreamoftheTAK1‐p38MAPKaxisinneutrophils,whereastheMEK/ERK,JNK,PI3K,andPKCpathwaysarenotinvolved.PharmacologicalblockadeofMNK1,aswellasoverexpressionexperiments,establishedthatcytokineproteinsynthesis(butnotgeneexpression)isunderthecontrolofMNK1inneutrophils.Likewise,MNK1inhibitionreversedtheantiapoptoticeffectofLPSandTNF‐αinneutrophils,andthiswasaccompaniedbyadecreasedexpressionoftheantiapoptoticproteinMcl‐1.Thus,MNK1appearstobeanimportantregulatorofneutrophilresponses.AlthoughMNK1inhibitiondidnotaffectproteinrecruitmenttomRNAcaps,itdecreasedthephosphorylationofmoleculesimplicatedintranslationinitiationcontrol,suchasS6K,S6,andhyperphosphorylated4E‐BP1.ThesemoleculartargetsofMNK1aresharedwiththoseofPI3Kinneutrophils,andaccordingly,MNK1inhibitionpartiallyimpairedthebelatedPI3K/AktactivationelicitedbyLPSorTNFinthesecells.Giventheimportanceofneutrophilsandtheirproductsinnumerouschronicinflammatorydisorders,MNK1couldrepresentanattractivetherapeutictarget...

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